The objective of Project 3 (Pretargeted Radioimmunotherapy for Hematologic Malignancies) is to improve the efficacy and diminish the toxicity of radioimmunotherapy (RIT) by removing the proportion of radioisotope that fails to bind to tumor and remains in the blood perfusing normal organs. This goal will be achieved by employing a multi-step pretargeted RIT (PRIT) approach in which conjugates of the anti-CD45 BCS Ab and streptavidin are injected first into patients with CD45-expressing hematologic malignancies followed by infusion of radiolabeled DOTA-biotin 48 hours later. In Aim 1, we will conduct a phase I trial of non-myeloablative allogeneic hematopoietic cell transplantation (HCT) using PRIT with BCS-SA and radiobiotin followed by fludarabine (FLU) and 2 Gy total body irradiation (TBI) for relapsed or refractory acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or high risk myelodysplasia (MDS). The primary objective of this Aim is to estimate the maximum tolerated dose (MTD) of [90]Y-DOTA-biotin when given with this transplant conditioning regimen. Secondary objectives include defining the pharmacokinetics (PK) and biodistributions of the BCS-SA and radiolabeled-DOTA-biotin reagents and examining their potential efficacy. In Aim 2, we will conduct a phase I trial of myeloablative autologous HCT for relapsed lymphoma using PRIT with BCS-SA and radiobiotin followed by etoposide (VP16) and cyclophosphamide (CY). The primary objective of this study is to estimate the MTD of [90]Y-DOTA-biotin using pre-targeting technology followed by autologous HCT in patients with relapsed lymphoma. In Aim 3 we will compare and contrast the biodistributions and dosimetries of radiobiotin pretargeted using anti-CD45 BCS-SA with those observed with directly radiolabeled anti-CD45 BCS Ab in patients with leukemia and lymphoma. The overall goal of Project 1 is to improve the delivery of radiation to tumor cells compared to normal tissues, thereby allowing escalation of the tumor dose while maintaining well-defined, tolerable upper limits on the doses to critical normal organs. Successful execution of this Project should lead to improvements in the cure rates of patients with relapsed and refractory AML, ALL, MDS and NHL undergoing HCT.